A Research Guide for
Castleman Disease

UCD involves a single lymph node or a single region of connected lymph nodes. It is the most common form, accounting for roughly half to two-thirds of all Castleman disease cases. UCD can occur anywhere in the body but is most often found in the chest (mediastinum), abdomen, or neck.

Most UCD patients have few or no systemic symptoms — the enlarged node is often discovered incidentally on imaging done for another reason. Some patients do have systemic symptoms (fatigue, fevers, lab abnormalities) driven by IL-6 production from the affected node, and these symptoms resolve after surgical removal.

The prognosis for UCD is excellent. Complete surgical excision is curative in the vast majority of cases, and recurrence after complete removal is uncommon. For the small number of patients where the node cannot be fully removed due to its location (such as deep retroperitoneal or mediastinal locations near vital structures), radiation therapy, embolization, or medical therapy with siltuximab or tocilizumab can control the disease.

iMCD involves enlarged lymph nodes in multiple body regions accompanied by systemic inflammatory symptoms: fevers, night sweats, fatigue, weight loss, fluid accumulation (edema, ascites, pleural effusions), and laboratory abnormalities (elevated CRP, anemia, low albumin, high immunoglobulins, elevated IL-6). The term “idiopathic” means the cause is unknown — by definition, iMCD is diagnosed only after HHV-8 infection has been excluded.

iMCD ranges in severity from mild disease manageable with anti-IL-6 therapy to severe, life-threatening disease with organ failure. The disease can follow a relapsing-remitting course or be persistently active. Without effective treatment, severe iMCD carries significant mortality. With modern targeted therapy, most patients achieve meaningful disease control.

The international consensus diagnostic criteria for iMCD (Fajgenbaum et al., Blood 2017) require: (1) enlarged lymph nodes in at least two lymph node stations, (2) characteristic histopathologic features on lymph node biopsy, and (3) at least two of eleven minor criteria spanning laboratory abnormalities, constitutional symptoms, and organ involvement — after excluding infections, autoimmune diseases, and malignancies that can mimic iMCD.

HHV-8 associated MCD is driven by human herpesvirus 8 (HHV-8, also called Kaposi sarcoma-associated herpesvirus or KSHV). The virus infects B cells in lymph nodes and produces a viral form of IL-6 (vIL-6) that drives lymph node enlargement and systemic inflammation. This form occurs predominantly in people living with HIV and in immunosuppressed individuals, though it can rarely occur in HIV-negative people in HHV-8 endemic regions.

HHV-8 MCD can be aggressive, with episodes of severe systemic inflammation (cytokine storms) that can be life-threatening. It also carries an increased risk of developing non-Hodgkin lymphoma (particularly primary effusion lymphoma and diffuse large B-cell lymphoma) and Kaposi sarcoma. Rituximab, which targets CD20-positive B cells including those harboring HHV-8, is the primary treatment and produces high response rates. Antiretroviral therapy for HIV is an essential component of management.

TAFRO syndrome differs from typical iMCD in several important ways. While classic iMCD tends to have elevated platelets, high immunoglobulins, and large lymph nodes, TAFRO syndrome characteristically has low platelets, normal or low immunoglobulins, relatively modest lymphadenopathy, and prominent fluid retention and organ dysfunction. TAFRO tends to present more acutely and can progress rapidly to organ failure if not treated urgently.

The underlying mechanism of TAFRO syndrome is not fully understood, but it appears to involve vascular endothelial growth factor (VEGF) signaling in addition to IL-6, which may explain the prominent vascular leak and fluid retention. Treatment often requires more aggressive initial therapy compared to typical iMCD, and response to anti-IL-6 therapy alone may be incomplete.

When evaluating any treatment claim for Castleman disease, ask these questions:

• Is the advice specific to your subtype (UCD, iMCD, or HHV-8 MCD)? Treatments differ fundamentally between subtypes.
• Does it come from a physician or center with specific Castleman disease experience?
• Is it supported by published evidence in peer-reviewed journals?
• Is it endorsed by the Castleman Disease Collaborative Network (CDCN) or reflected in international consensus guidelines?
• Could it interfere with standard treatment?

Be especially cautious of anyone who suggests abandoning standard medical therapy for unproven alternatives. iMCD and HHV-8 MCD can be life-threatening without proper treatment, and delays caused by pursuing ineffective therapies have real consequences.

• Bring a second person to every appointment. One listens and asks questions; the other writes things down.
• Ask permission to record. Most clinics allow phone recording if asked first.
• Keep a single folder — paper or digital — with every report: pathology, imaging, blood work, and treatment records. You will be asked for these repeatedly, especially for second opinions.
• Contact the CDCN early. The Castleman Disease Collaborative Network (cdcn.org) provides patient navigation, connects patients to expert physicians, and maintains the most current treatment information. Their resources are free.

• ☐ Diagnosis confirmed on lymph node biopsy by an expert hematopathologist
• ☐ Subtype determined: UCD, iMCD, or HHV-8 MCD
• ☐ HHV-8 testing completed (LANA-1 immunohistochemistry on biopsy and/or HHV-8 PCR blood test)
• ☐ HIV testing completed (mandatory for all patients)
• ☐ Full laboratory workup: CBC, CRP, ESR, IL-6 (if available), albumin, immunoglobulins, creatinine, LDH, ferritin
• ☐ CT scan of chest, abdomen, and pelvis (or PET-CT) to map lymph node involvement
• ☐ For multicentric disease: assess for organ dysfunction (renal, hepatic, pulmonary)
• ☐ CDCN contacted for patient navigation support (cdcn.org)
• ☐ Expert center or specialist identified — confirm Castleman disease experience
• ☐ Records folder started: pathology, imaging, labs in one place
• ☐ Second opinion considered, especially if the diagnosis is uncertain or treatment is complex

Pathologists recognize several histologic patterns in Castleman disease:

• Hyaline vascular: The most common pattern in UCD. Characterized by regressed germinal centers with hyalinized blood vessels penetrating the follicle centers (“lollipop” pattern) and expanded mantle zones forming concentric rings (“onion-skinning”).
• Plasmacytic: More common in multicentric disease. Characterized by expanded interfollicular areas filled with sheets of plasma cells.
• Mixed: Features of both patterns.
• Hypervascular: Seen in some iMCD cases, particularly TAFRO syndrome.

Expert hematopathology review is strongly recommended because the histologic features can overlap with lymphoma, autoimmune conditions, and reactive lymphadenopathy. Misdiagnosis is common, particularly at centers that see Castleman disease infrequently.

• HHV-8 testing: Critical for distinguishing iMCD from HHV-8 MCD. Testing includes LANA-1 immunohistochemistry on the lymph node biopsy and HHV-8 viral load by PCR in blood. This must be done in all multicentric cases.
• HIV testing: Required in all patients because HHV-8 MCD is strongly associated with HIV, and HIV status affects treatment decisions.
• Blood tests: Complete blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), IL-6 level (where available), serum albumin, total protein, immunoglobulin levels (IgG, IgA, IgM), creatinine, liver function, LDH, ferritin, fibrinogen.
• Imaging: CT of the chest, abdomen, and pelvis to assess the number and distribution of enlarged lymph nodes and to identify organ enlargement. PET-CT may be used to evaluate metabolic activity and help distinguish from lymphoma.
• Bone marrow biopsy: Not required for all patients but important in TAFRO syndrome (to assess reticulin fibrosis) and when lymphoma is being considered in the differential diagnosis.

Part of diagnosing Castleman disease is ruling out other conditions that can look similar. This is especially important for iMCD, which shares features with several other diseases:

• Lymphoma (particularly Hodgkin lymphoma and follicular lymphoma)
• Autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis)
• IgG4-related disease
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes)
• Infections (tuberculosis, EBV)
• Hemophagocytic lymphohistiocytosis (HLH)

The international consensus criteria require that these mimics be systematically excluded before an iMCD diagnosis is made.

• A hematologist or hematologist-oncologist with specific Castleman disease experience
• Access to expert hematopathology for biopsy review
• Familiarity with anti-IL-6 therapy (siltuximab, tocilizumab) and the international consensus treatment guidelines
• An active clinical trials program, especially trials through the CDCN or ACCELERATE registry
• For TAFRO syndrome: ICU-level care capability for severe presentations

The CDCN maintains a physician directory of Castleman disease experts and can help connect patients to appropriate specialists. Contact them at cdcn.org.

A second opinion is especially valuable in Castleman disease because misdiagnosis is common and treatment varies significantly by subtype. The pathology slides from the original biopsy should be sent for expert review. Many expert centers offer remote pathology review and virtual consultations. The CDCN can facilitate these connections.

Complete surgical excision (removal) of the affected lymph node or lymph node group is the standard treatment for UCD and is curative in the vast majority of cases. After complete removal, recurrence is rare. Patients who had systemic symptoms (fevers, fatigue, lab abnormalities) typically see these resolve completely after surgery.

The operation is usually performed by a general surgeon, thoracic surgeon, or surgical oncologist, depending on the location of the node. For chest (mediastinal) masses, video-assisted thoracoscopic surgery (VATS) or robotic approaches are often possible.

In a small minority of UCD cases, the lymph node mass is in a location that makes complete removal unsafe — such as deep in the retroperitoneum or encasing major blood vessels. Options for unresectable UCD include:

• Radiation therapy: Can produce durable responses for localized disease that cannot be removed surgically.
• Arterial embolization: Cutting off the blood supply to the mass before surgery or as a standalone treatment.
• Anti-IL-6 therapy: Siltuximab or tocilizumab to control symptoms and potentially shrink the mass, especially if the patient has IL-6-driven systemic symptoms.
• Observation: For asymptomatic, unresectable UCD that is not causing problems, careful monitoring may be appropriate.

After complete surgical removal, follow-up typically includes periodic clinical examinations and imaging (usually CT) to confirm no recurrence. The follow-up schedule varies, but many centers check at 6 months, 12 months, and then annually for several years. Blood tests (CRP, CBC) are checked to confirm normalization. Long-term prognosis after complete excision is excellent.

Questions to ask your surgeon: Was the entire mass removed with clear margins? What does the pathology report show? What is the recommended follow-up schedule?

For non-severe iMCD, anti-IL-6 therapy is the recommended first-line treatment:

• Siltuximab (Sylvant): The only FDA-approved drug for iMCD. It is a monoclonal antibody that directly binds and neutralizes IL-6. Given as an intravenous infusion every 3 weeks. The pivotal phase II trial demonstrated durable complete and partial responses in the majority of treated patients, with sustained improvements in symptoms, laboratory abnormalities, and lymph node size. Siltuximab is generally well tolerated; the most common side effects include upper respiratory infections, fatigue, and itching.
• Tocilizumab (Actemra): A monoclonal antibody that blocks the IL-6 receptor rather than IL-6 itself. Approved for iMCD in Japan but used off-label in other countries. Given as an intravenous infusion every 2–4 weeks or by subcutaneous injection. It is an alternative when siltuximab is not available or not tolerated.

Anti-IL-6 therapy is typically continued indefinitely as maintenance, since iMCD often relapses when treatment is stopped. Some patients achieve deep, sustained remissions on long-term therapy.

Severe iMCD — defined by significant organ dysfunction (renal failure, severe anemia, respiratory compromise, massive fluid retention) — requires urgent initial treatment. The consensus guidelines recommend:

• High-dose corticosteroids (such as dexamethasone or methylprednisolone) for rapid symptom control
• Siltuximab or tocilizumab initiated concurrently
• Intensive supportive care: fluid management, transfusions, and possibly ICU-level monitoring

If anti-IL-6 therapy plus corticosteroids does not produce adequate improvement within weeks, the guidelines recommend escalation to cytotoxic chemotherapy or immunosuppressive agents.

Roughly one-third of iMCD patients do not respond adequately to anti-IL-6 therapy, suggesting their disease is driven by pathways other than IL-6 alone. For these patients, second-line options include:

• Rituximab: Anti-CD20 antibody; used alone or in combination. Can be effective in some cases.
• Sirolimus (rapamycin): An mTOR inhibitor showing promise based on CDCN-supported research identifying the mTOR pathway as active in some iMCD cases. The SAPHYR trial (NCT03933904) is evaluating sirolimus for anti-IL-6-refractory iMCD.
• Cytotoxic chemotherapy: Regimens such as R-CHOP, CVAD, or single-agent etoposide for life-threatening cases unresponsive to other treatments.
• Thalidomide or lenalidomide: Immunomodulatory agents that have shown activity in case series.
• Bortezomib: A proteasome inhibitor with reported activity in refractory cases.

Treatment decisions beyond first-line are highly individualized and should involve a Castleman disease expert. Clinical trial participation is strongly encouraged for patients who do not respond to anti-IL-6 therapy.

Patients on treatment for iMCD require regular monitoring:

• Blood tests every 1–3 months: CBC, CRP, albumin, immunoglobulins, creatinine, liver function
• IL-6 levels where available (note: siltuximab can cause IL-6 levels to appear elevated due to drug-bound IL-6 accumulation; CRP is a more reliable activity marker during siltuximab therapy)
• Imaging (CT) every 3–6 months initially, then less frequently once stable
• Assessment of symptoms: fatigue, fevers, weight, fluid retention

The CDCN has developed a disease severity scoring system and response criteria to help clinicians track treatment effectiveness.

Rituximab is the first-line treatment for HHV-8 MCD and has transformed outcomes for this disease. It works by depleting CD20-positive B cells, including those harboring HHV-8.

• Standard dosing: Rituximab 375 mg/m² given intravenously once weekly for 4 weeks.
• Response rates: Overall response rates exceed 90% in published series. Most patients achieve sustained remissions.
• Relapse: Some patients relapse and can be successfully re-treated with rituximab.

For severe or refractory HHV-8 MCD, rituximab may be combined with liposomal doxorubicin or other chemotherapy agents. In patients with concurrent Kaposi sarcoma, the combination of rituximab and liposomal doxorubicin is often used because rituximab alone can sometimes cause Kaposi sarcoma flares.

For patients with HIV-associated HHV-8 MCD, optimized antiretroviral therapy (ART) is an essential component of treatment. Effective viral suppression with ART improves immune function and reduces the risk of HHV-8 MCD flares. All patients with HHV-8 MCD should be on ART regardless of CD4 count.

Patients with HHV-8 MCD have an elevated risk of developing non-Hodgkin lymphoma, particularly primary effusion lymphoma and diffuse large B-cell lymphoma. Regular monitoring with clinical examinations, blood tests, and periodic imaging is important. New or rapidly growing lymph nodes, rising LDH, or new B symptoms should prompt evaluation for lymphoma.

The initial management of TAFRO syndrome typically involves:

• High-dose corticosteroids: Pulse methylprednisolone (e.g., 500–1000 mg daily for 3 days) followed by high-dose oral prednisone with slow taper.
• Anti-IL-6 therapy: Siltuximab or tocilizumab initiated early.
• Aggressive supportive care: Platelet transfusions if severe thrombocytopenia with bleeding, drainage of effusions, fluid management, and potentially ICU admission.
• Cyclosporine: Often added, particularly based on the Japanese experience, for patients with inadequate response to steroids and anti-IL-6 therapy alone.

TAFRO syndrome that does not respond to the initial combination may require escalation to:

• Rituximab
• Sirolimus
• Cytotoxic chemotherapy (etoposide, cyclophosphamide-based regimens)
• Plasma exchange in severe cases with cytokine storm features

TAFRO management is complex and should involve a center with specific experience in this condition. Japanese centers have the most published experience with TAFRO syndrome.

• Can the mass be completely removed surgically? If not, why?
• What surgical approach will be used (open, minimally invasive)?
• What is the plan if the mass cannot be completely removed?
• What follow-up schedule do you recommend after surgery?

• How severe is my disease based on the consensus criteria?
• Do you recommend siltuximab or tocilizumab, and why?
• What are the signs that treatment is working, and how will you measure response?
• What is the plan if anti-IL-6 therapy does not work?
• Will I need to stay on treatment indefinitely?
• Are there clinical trials I should consider, including the SAPHYR trial?
• Have you treated other iMCD patients? If not, can you connect me to a center that has?

• Is my HIV well controlled on current antiretroviral therapy?
• What rituximab regimen do you recommend?
• Do I have or am I at risk for Kaposi sarcoma?
• How will you monitor for lymphoma?
• What is the plan if the disease relapses after rituximab?

The CDCN-led research has identified activation of the mTOR signaling pathway in iMCD lymph node tissue. Sirolimus (rapamycin), an mTOR inhibitor already FDA-approved for organ transplant rejection, is being evaluated in the SAPHYR trial (NCT03933904) for iMCD patients who have not responded to anti-IL-6 therapy. Early results have been promising, with some patients achieving meaningful clinical and laboratory responses.

Janus kinase (JAK) inhibitors (such as ruxolitinib and others) block the intracellular signaling downstream of IL-6 and other cytokines. Because IL-6 signals through the JAK-STAT pathway, JAK inhibitors have a strong scientific rationale in Castleman disease. Case reports and small series have described responses in refractory iMCD, and formal clinical investigation is underway.

For patients with severe or refractory iMCD, combinations of anti-IL-6 therapy with other immunomodulatory agents are being explored. These include combinations of siltuximab with sirolimus, rituximab with anti-IL-6 therapy, and novel multi-target strategies. The CDCN is coordinating these efforts through its ACCELERATE natural history study and clinical trial network.

One of the most important open questions in iMCD research is understanding what drives disease in the approximately one-third of patients who do not respond to IL-6 blockade. The CDCN has identified several candidate pathways including mTOR, VEGF, and interferon signaling. Better understanding of these pathways is expected to lead to more targeted treatments for anti-IL-6-refractory disease.

Fatigue is one of the most common and debilitating symptoms of iMCD, even with effective treatment. Strategies that help include structured regular exercise (even light activity such as walking), adequate sleep hygiene, pacing activities to avoid boom-and-bust cycles, treating underlying anemia if present, and addressing mood and anxiety. An occupational therapist can help develop energy-conservation strategies.

Both the disease itself and its treatments (siltuximab, rituximab, corticosteroids) can suppress immune function and increase infection risk. Practical steps include staying current on vaccinations (discuss timing relative to rituximab, which depletes B cells and impairs vaccine responses), practicing hand hygiene, reporting fevers promptly, and discussing prophylactic medications with the treating team when on immunosuppressive therapy.

Living with a rare disease can be isolating. Many Castleman disease patients describe frustration with physicians who have never heard of their diagnosis, difficulty explaining the condition to others, and anxiety about disease flares. Connecting with the Castleman disease patient community through the CDCN provides support from people who understand the experience. Professional psychological support, including counseling or therapy, can be valuable. Ask the treating team for a referral if needed.

Patients with multicentric forms of Castleman disease require long-term monitoring even when in remission. This includes regular blood tests (CBC, CRP, albumin, immunoglobulins), periodic imaging, and clinical assessments. Long-term risks to discuss with the medical team include secondary malignancies (particularly lymphoma in HHV-8 MCD), AA amyloidosis in chronically inflamed cases, and the effects of long-term immunosuppressive therapy.

For patients with severe iMCD or TAFRO syndrome, caregivers carry a heavy load during acute disease episodes. Key strategies include building a support team rather than relying on a single caregiver, setting up practical help early, using coordination platforms like CaringBridge, and accessing caregiver resources through the CDCN patient community and organizations like the Family Caregiver Alliance (caregiver.org, 800-445-8106).

One unique challenge of Castleman disease is that most people — including many healthcare providers — have never heard of it. Having a brief, clear explanation ready can be helpful: “Castleman disease is a rare condition where the immune system causes lymph nodes to grow abnormally. It is not cancer, but it can cause serious problems and needs ongoing treatment.” The CDCN provides patient-friendly educational materials that can be shared with family, friends, and local healthcare providers.

The outlook for Castleman disease has improved significantly in recent years. UCD is almost always curable with surgery. For iMCD, the availability of siltuximab and tocilizumab has transformed a previously devastating disease into one that most patients can live with on chronic treatment. HHV-8 MCD, once frequently fatal, now has response rates exceeding 90% with rituximab. The CDCN is driving research at a pace unusual for a rare disease, with new treatments in the pipeline. There is genuine reason for hope — tempered by the reality that some patients have refractory disease and that more research is needed.

• UCD: Excellent. Surgical cure in the vast majority. Even when not resectable, the disease is typically well controlled with medical therapy.
• iMCD (non-severe): Most patients respond to anti-IL-6 therapy and achieve stable, manageable disease. Life expectancy for responders approaches normal with ongoing treatment.
• iMCD (severe / TAFRO): The most challenging form. Acute episodes can be life-threatening and require intensive treatment. With modern management at expert centers, many patients are stabilized, but the disease can be unpredictable and refractory cases remain difficult.
• HHV-8 MCD: Very good with rituximab treatment. Long-term monitoring for lymphoma is important.

• What subtype of Castleman disease do I have — UCD, iMCD, or HHV-8 MCD?
• Has HHV-8 and HIV testing been completed? What were the results?
• Has my biopsy been reviewed by a hematopathologist with Castleman disease experience?
• How severe is my disease, and what organs are affected?
• How many Castleman disease patients have you treated?
• Should I contact the CDCN for patient navigation support?
• Should I seek a second opinion at a Castleman expert center?

• What is the realistic range of outcomes for my specific subtype and severity?
• Will I need treatment for the rest of my life?
• What should I watch for between visits — what symptoms mean I should call right away?
• Are there clinical trials I should consider?
• What is the most useful thing my family can do to support my care?

• Janssen CarePath (for Sylvant/siltuximab): Copay assistance program for eligible commercially insured patients. 844-795-8268. janssencarepath.com
• Genentech Access Solutions (for Rituxan/rituximab): Financial assistance programs. 866-422-2377. genentech-access.com
• Patient Access Network Foundation (PAN): Copay assistance for qualifying patients. 866-316-7263. panfoundation.org
• HealthWell Foundation: Copay assistance for specific medications. 800-675-8416. healthwellfoundation.org

• Patient Advocate Foundation: Case management, copay relief, insurance navigation. 800-532-5274. patientadvocate.org
• CancerCare: Financial grants and counseling. 800-813-4673. cancercare.org
• NeedyMeds: Database of prescription-assistance programs. 800-503-6897. needymeds.org
• Family Reach: Emergency financial help for families facing serious illness. familyreach.org
• Social Security Disability: 800-772-1213. ssa.gov. Severe Castleman disease may qualify under compassionate allowances.

• Castleman Disease Collaborative Network (CDCN): The central resource for patients, families, and physicians. Patient navigation, clinical trial matching, physician directory, educational materials, patient community, research updates. cdcn.org
• National Organization for Rare Disorders (NORD): Rare disease assistance programs. 203-744-0100. rarediseases.org
• Global Genes: Rare disease patient advocacy and resources. globalgenes.org

Siltuximab (Sylvant) received FDA approval in April 2014 for the treatment of multicentric Castleman disease in patients who are HIV-negative and HHV-8-negative — effectively, for iMCD. The FDA approval was based on a randomized, placebo-controlled phase II trial demonstrating a durable tumor and symptomatic response rate significantly higher than placebo. Rituximab is FDA-approved for other indications (lymphoma, rheumatoid arthritis) and is used off-label for HHV-8 MCD.

Siltuximab received EMA approval in May 2014. It is available across EU member states, though national reimbursement varies. In the UK, siltuximab access is through the NHS with specialist commissioning arrangements for rare diseases. NICE has not issued a formal technology appraisal for siltuximab due to the rarity of the condition, but it is available through specialist centers.

Tocilizumab is approved for iMCD in Japan and is used as the standard anti-IL-6 therapy. Japan has the most extensive published experience with TAFRO syndrome and has developed detailed treatment algorithms for this subtype. Japanese treatment guidelines may differ from US and European approaches, particularly in the use of cyclosporine for TAFRO syndrome.

Siltuximab (Sylvant) is approved by Health Canada (Notice of Compliance, December 2014) for HIV-negative, HHV-8-negative iMCD — it was the first treatment approved in Canada for MCD. Provincial formulary coverage varies and may require prior authorization. Rituximab is widely available for HHV-8 MCD through standard formulary channels.

Siltuximab availability is expanding but remains limited in many low- and middle-income countries. In regions where siltuximab is not available, tocilizumab (which has broader global availability due to its rheumatoid arthritis indication) is often used as an alternative. The CDCN can help connect patients in underserved regions to compassionate-use programs and international expert consultation.

• Interferon-alpha for iMCD DE-ADOPTED
  Previously used before anti-IL-6 therapy became available. Response rates were modest and side effects significant (depression, fatigue, cytopenias). Superseded by siltuximab and tocilizumab.
• Anti-IL-1 therapy (anakinra) as monotherapy for iMCD FAILED
  Interleukin-1 blockade was investigated based on the hypothesis that IL-1 drives IL-6 production in iMCD. Published case reports showed inconsistent results, and IL-1 blockade has not demonstrated reliable efficacy as monotherapy.
• High-dose chemotherapy with stem cell transplant for iMCD DE-ADOPTED
  Before targeted therapies, autologous stem cell transplant was attempted for refractory iMCD. Results were mixed, treatment-related mortality was significant, and many patients relapsed. With effective targeted therapy now available, stem cell transplant is no longer considered a standard approach.
• Corticosteroid monotherapy for iMCD maintenance DE-ADOPTED
  While corticosteroids are useful for acute disease control, long-term maintenance with steroids alone produces significant toxicity (osteoporosis, diabetes, infections, weight gain) without addressing the underlying disease driver. Anti-IL-6 therapy is the preferred long-term approach and is steroid-sparing.

• AA amyloidosis — a condition where chronic inflammation leads to deposits of abnormal protein (amyloid) in organs; a rare complication of long-standing iMCD.
• Anasarca — generalized, severe fluid retention causing swelling throughout the body; a hallmark of TAFRO syndrome.
• Anti-IL-6 therapy — drugs that block interleukin-6 or its receptor; the primary targeted treatment for iMCD.
• Ascites — abnormal fluid accumulation in the abdomen.
• B cells — a type of white blood cell that produces antibodies; the target of rituximab.
• CD20 — a protein on the surface of B cells; the target of rituximab.
• CDCN — Castleman Disease Collaborative Network; the leading patient advocacy and research organization for Castleman disease.
• CRP — C-reactive protein; a blood marker of inflammation, used to monitor disease activity.
• Cytokine — a signaling molecule that coordinates immune responses; IL-6 is the most important cytokine in Castleman disease.
• Cytokine storm — a dangerous overactivation of the immune system with excessive cytokine release, causing organ damage.
• Excisional biopsy — surgical removal of an entire lymph node for diagnostic evaluation; the preferred biopsy type for diagnosing Castleman disease.
• HHV-8 — human herpesvirus 8, also called Kaposi sarcoma-associated herpesvirus (KSHV); causes one form of multicentric Castleman disease.
• Hyaline vascular — a histopathologic pattern commonly seen in UCD; characterized by distinctive blood vessel and lymphoid follicle changes.

• IL-6 (interleukin-6) — a cytokine that plays a central role in driving inflammation and lymph node enlargement in most forms of Castleman disease.
• iMCD — idiopathic multicentric Castleman disease; the form involving multiple lymph node regions with unknown cause.
• Immunoglobulins — antibodies produced by B cells; often elevated in iMCD (except in TAFRO, where they may be normal or low).
• LANA-1 — latency-associated nuclear antigen 1; an HHV-8 protein detected by immunohistochemistry on biopsy tissue to diagnose HHV-8 infection.
• Lymphadenopathy — enlarged lymph nodes.
• Lymphoproliferative disorder — a condition involving abnormal proliferation of lymphoid tissue; Castleman disease is a lymphoproliferative disorder that is not cancer.
• mTOR — a cell-signaling pathway involved in cell growth; targeted by sirolimus; found to be activated in some iMCD cases.
• Organomegaly — abnormal enlargement of organs, particularly the spleen and liver.
• Plasmacytic — a histopathologic pattern characterized by abundant plasma cells; more common in multicentric disease.
• Pleural effusion — fluid accumulation around the lungs.
• Reticulin fibrosis — scarring (fibrosis) in the bone marrow, seen in TAFRO syndrome.
• Rituximab — an anti-CD20 monoclonal antibody that depletes B cells; the primary treatment for HHV-8 MCD.

• Siltuximab (Sylvant) — a monoclonal antibody that binds and neutralizes IL-6; the only FDA-approved drug for iMCD.
• Sirolimus (rapamycin) — an mTOR inhibitor being investigated for anti-IL-6-refractory iMCD.
• TAFRO syndrome — a severe subtype of iMCD defined by Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis, and Organomegaly.
• Thrombocytopenia — low platelet count; a defining feature of TAFRO syndrome.
• Tocilizumab (Actemra) — a monoclonal antibody that blocks the IL-6 receptor; used as an alternative to siltuximab for iMCD.
• UCD — unicentric Castleman disease; the form involving a single lymph node region, usually cured by surgery.
• VEGF — vascular endothelial growth factor; thought to play a role in TAFRO syndrome's vascular leak and fluid retention.
• vIL-6 — viral interleukin-6; a form of IL-6 produced by HHV-8 that drives inflammation in HHV-8 MCD.

Guidelines and consensus documents:

• Fajgenbaum DC et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-1657.
• van Rhee F et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 2018;132(20):2115-2124.
• Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020;135(16):1353-1364.
• Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018;132(22):2323-2330.
• Masaki Y et al. Proposed diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome. Int J Hematol. 2016;103(6):686-692.

Key trials and studies:

• Castleman Disease Collaborative Network (CDCN) (cdcn.org) — The primary patient resource. Patient navigation, physician directory, clinical trial matching, educational materials, research updates.
• PubMed (pubmed.ncbi.nlm.nih.gov) — Free public database of medical research.
• ClinicalTrials.gov (clinicaltrials.gov) — Official U.S. registry of clinical trials.
• National Organization for Rare Disorders (NORD) (rarediseases.org) — Rare disease resources, assistance programs, community.
• National Cancer Institute (cancer.gov) — Information and trial search (1-800-4-CANCER).